Evaluation of Testosterone Undecanoate for Neuroprotection and Myelin Repair in Relapsing Remitting Multiple Sclerosis Patients

The primary objective of this study is to evaluate the **remyelinating** and neuroprotective effects of testosterone treatment over a 54-week period in patients with Relapsing Remitting Multiple Sclerosis (RRMS) who are concurrently treated with natalizumab, fingolimod, ponesimod, ocrelizumab, or ofatumumab. This evaluation focuses on a composite criterion that includes the analysis of thalamus atrophy and diffusion tensor imaging as measured by MRI. The clinical relevance of this objective lies in its potential to enhance therapeutic strategies aimed at neuroprotection and myelin repair, which are critical in managing RRMS and improving patient outcomes.

Secondary objectives include:

• Evaluating the effectiveness of the treatment on advanced parameters in MRI.
• Assessing the clinical effectiveness of the treatment and its tolerance.
• Identifying new biomarkers predictive of the disease's evolution through the establishment of a biobank of blood samples.

The clinical trial focuses on evaluating the effects of testosterone treatment in patients with **Relapsing Remitting Multiple Sclerosis** (RRMS). The study population consists exclusively of male participants aged between 18 and 55 years. Participants are required to have a confirmed diagnosis of multiple sclerosis as per the revised McDonald criteria and must have been on a stable regimen of disease-modifying therapies such as natalizumab, fingolimod, ponesimod, ocrelizumab, or ofatumumab for at least one year prior to randomization. The trial excludes individuals with recent relapses or unstable neurological conditions. Participants must also exhibit biological hypogonadism, defined by serum total testosterone levels below 20 nmol/L. The sponsor has not provided information regarding the total number of participants. The trial does not include female subjects or vulnerable populations, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **remyelinating** and neuroprotective effects of **testosterone undecanoate** in patients with **relapsing-remitting multiple sclerosis** (RRMS). This is a Phase 4, randomized, double-blind, controlled study comparing the active treatment, NEBIDO 1000 mg/4 ml solution for injection, with a placebo. The trial is expected to last for 54 weeks, with participant involvement spanning the same duration. The primary endpoint is a binary criterion comparing the success rate in each treatment group, defined by thalamic atrophy less than 0.5% per year and/or a decrease in transverse diffusivity in lesions less than 0.5% per year. Secondary endpoints include the efficiency of treatment by imaging, clinical efficiency, and the safe use of the treatment.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, confirmed diagnosis of RRMS, and biological hypogonadism. Follow-up visits will be conducted at regular intervals to monitor treatment effects, assess safety, and collect data on primary and secondary endpoints. The end-of-study visit will conclude the trial, where final assessments will be made. Conditions that may lead to early termination from the study include the occurrence of significant adverse events, withdrawal of consent, or any condition that, in the investigator's opinion, warrants discontinuation for the participant's safety.

The clinical trial involves the administration of **NEBIDO 1000 mg/4 ml**, a **solution for injection** containing the active substance **testosterone undecanoate**. This pharmaceutical product is manufactured by Laboratoires Grünenthal S.A.S. and is authorized in France under the marketing authorization number 34009 367 582 7 8. NEBIDO is administered via **intramuscular use**. The dosing regimen involves a maximum daily dose of 1000 mg, with a total maximum dose of 6000 mg over the course of the study. The treatment period extends up to 54 weeks. The ampoules of NEBIDO are blinded for the purpose of the trial to ensure unbiased results.

The study also includes a **placebo** treatment, referred to as "Placebo to Nebido." The placebo is designed to mimic the appearance and administration route of the active treatment, NEBIDO, to maintain the integrity of the double-blind study design. The placebo does not contain any active pharmaceutical ingredients and is used to assess the efficacy and safety of the experimental treatment by providing a baseline for comparison.

The efficacy of the treatment in the clinical trial titled "TestOsterone TreatmEnt on Neuroprotection and Myelin Repair in Relapsing Remitting Multiple Sclerosis (TOTEM-RRMS)" will be assessed using a combination of primary and secondary endpoints. The primary endpoint is a binary criterion comparing the success rate in each treatment group, defined by **thalamic atrophy** less than 0.5% per year and/or a decrease in transverse diffusivity in lesions less than 0.5% per year. This will be measured using MRI imaging techniques.

Secondary endpoints will evaluate the efficiency of treatment through various imaging and clinical parameters. Imaging assessments will include the evolution of conventional MRI parameters such as the volume and number of T1 hypointense lesions, the volume and number of new or enlarged T2 lesions, and the total volume of hyper-intensity FLAIR. Unconventional MRI parameters will also be evaluated, including diffusion tensor imaging (NODDI) and quantitative magnetization transfer imaging (MPF).

Clinical efficiency will be assessed using several tools and questionnaires. These include the Brief International Cognitive Assessment for Multiple Sclerosis, which consists of the Symbol Digit Modalities Test, the California Verbal Learning Test Second Edition, and the Brief Visuospatial Memory Test Revised. Changes in quality of life and health-related quality of life will be measured by the SF-36 and EQ-5D questionnaires, respectively. The impact of multiple sclerosis on workplace productivity and day-to-day activities will be assessed by the WPAI (Work Productivity and Activity Impairment) questionnaire. Fatigue will be measured using the Multi-Dimensional Fatigue Impact Scale (MFIS), and anxiety and depression will be evaluated using the Hospital Anxiety and Depression Scale (HADS). The evolution of handicap will be assessed by the EDSS Score.

Safety and tolerability of the treatment will also be monitored, including the number and nature of adverse events, evaluation of vital signs at each visit, clinical and neurological examinations, biological results, and locally interpreted MRI for tolerance. Monitoring of concomitant medications will be conducted outside of Tysabri® treatment. The trial is planned to last for 54 weeks, with assessments scheduled at various timepoints throughout the study duration.